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Chapter 18

Regulation of Gene Expression

Lecture Outline

Overview: Conducting the Genetic Orchestra

Both prokaryotes and eukaryotes alter their patterns of gene expression in response tochanges in environmental conditions.

In multicellular eukaryotes, each cell type contains the same genome but expresses a differentsubset of genes.

During development, gene expression must be carefully regulated to ensure that the rightgenes are expressed only at the correct time and in the correct place.

Gene expression in eukaryotes and bacteria is often regulated at the transcription stage.

Control of other levels of gene expression is also important.

!" molecules play many roles in regulating eukaryotic gene expressions.

Disruptions in gene regulation can lead to cancer.

Concept 18.1 Bacteria often respond to environmental change ! regulatingtranscription.

!atural selection favors bacteria that express only those genes #hose products are needed bythe cell.

" bacterium in a tryptophan$rich environment that stops producing tryptophan conservesits resources.

%etabolic control occurs on t#o levels.

&irst, cells can ad'ust the activity of en(ymes already present.

)his may happen byfeedback inhibition, in #hich the activity of the first en(yme in apath#ay is inhibited by the path#ay*s end product.

&eedback inhibition, typical of anabolic +biosynthetic path#ays, allo#s a cell to adapt toshort$term fluctuations in the supply of a needed substance.

-econd, cells can vary the number of specific en(yme molecules they make by regulatinggene expression.

Genes of the bacterial genome may be s#itched on or off by changes in the metabolicstatus of the cell.

)he basic mechanism for the control of gene expression in bacteria, kno#n as the operonmodel, #as described by &rancois acob and ac/ues %onod in 0120.

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The operon model controls tryptophan synthesis.

Escherichia colisynthesi(es tryptophan from a precursor molecule in a series of steps, #itheach reaction cataly(ed by a specific en(yme.

)he five genes coding for these en(ymes are clustered together on the bacterial chromosomeas a transcription unit, served by a single promoter.

)ranscription gives rise to one long m!" molecule that codes for all five en(ymes in thetryptophan path#ay.

)he m!" is punctuated #ith start and stop codons that signal #here the coding se/uencefor each polypeptide begins and ends.

" key advantage of grouping genes #ith related functions into one transcription unit is that asingle on$off s#itch can control a cluster of functionally related genes.

In other #ords, these genes are under coordinate control.

3hen anE. colicell must make tryptophan for itself, all the en(ymes are synthesi(ed at onetime.

)he s#itch is a segment of D!" called an operator.

)he operator, located bet#een the promoter and the en(yme$coding genes, controls the accessof !" polymerase to the genes.

)he operator, the promoter, and the genes they control constitute an operon.

)he trpoperon +trp for tryptophan is one of many operons in theE. coligenome.

By itself, an operon is turned on. !" polymerase can bind to the promoter and transcribethe genes.

)he operon can be s#itched off by a protein called the trp repressor.

)he repressor binds to the operator, blocks attachment of !" polymerase to thepromoter, and prevents transcription of the operon*s genes.

4ach repressor protein recogni(es and binds only to the operator of a particular operon. )he trp repressor is the product of a regulator! gene called trpR, #hich is located at some

distance from the operon it controls and has its o#n promoter.

egulatory genes are transcribed continuously at slo# rates, and a fe# trp repressormolecules are al#ays present in anE. coli cell.

3hy is the trp operon not s#itched off permanently5

&irst, binding by the repressor to the operator is reversible.

"n operator vacillates bet#een t#o states, #ith and #ithout a repressor bound to it.

-econd, repressors contain allosteric sites that change shape depending on the binding ofother molecules.

)he trp repressor has t#o shapes6 active and inactive.

In the case of the trpoperon, #hen concentrations of tryptophan in the cell are high, sometryptophan molecules bind as a corepressorto the repressor protein.

)his activates the repressor and turns the operon off.

"t lo# levels of tryptophan, most of the repressors are inactive, and the operon is transcribed.

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"s tryptophan accumulates, more tryptophan molecules associate #ith trp repressormolecules, #hich bind to the trp operator and shut do#n production of the en(ymes of thetryptophan path#ay.

There are two types of operons: repressible and inducible.

)he trpoperon is an example of a repressibleoperon, one that is inhibited #hen a specific

small molecule +tryptophan binds allosterically to a regulatory protein. In contrast, an inducibleoperon is stimulated or induced #hen a specific small molecule

interacts #ith a regulatory protein.

In inducible operons, the regulatory protein is active +inhibitory as synthesi(ed, and theoperon is off.

"llosteric binding by an inducer molecule makes the regulatory protein inactive, and theoperon is turned on.

)he lacoperon contains a series of genes that code for en(ymes that play a ma'or role in thehydrolysis and metabolism of lactose +milk sugar.

In the absence of lactose, this operon is off because an active repressor binds to the operator

and prevents transcription. 7actose metabolism begins #ith hydrolysis of lactose into its component monosaccharides,

glucose and galactose. )his reaction is cataly(ed by the en(yme 8$galactosidase.

9nly a fe# molecules of $galactosidase are present in anE. colicell gro#n in the absence oflactose.

If lactose is added to the bacterium*s environment, the number of 8$galactosidase moleculesincreases by a thousandfold #ithin 0: minutes.

)he gene for 8$galactosidase is part of the lacoperon, #hich includes t#o other genes codingfor en(ymes that function in lactose metabolism.

)he regulatory gene, lacI, located outside the operon, codes for an allosteric repressor proteinthat can s#itch off the lacoperon by binding to the operator.

;nlike the trpoperon, the lacrepressor is active all by itself, binding to the operator ands#itching the lacoperon off.

"n inducerinactivatesthe repressor.

3hen lactose is present in the cell, allolactose, an isomer of lactose, binds to therepressor.

)his inactivates the repressor, and the lacoperon can be transcribed.

Repressible enzymesgenerally function in anabolic path#ays, synthesi(ing end products fromra# materials.

3hen the end product is present in sufficient /uantities, the cell can allocate its resources

to other uses. Inducible enzymesusually function in catabolic path#ays, digesting nutrients to simpler

molecules.

By producing the appropriate en(ymes only #hen the nutrient is available, the cell avoidsmaking proteins that have nothing to do.

Both repressible and inducible operons demonstrate negativecontrol of genes because activerepressors s#itch off the active form of the repressor protein.

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Some gene regulation is positive.

Positivegene control occurs #hen a protein molecule interacts directly #ith the genome tos#itch transcription on.

)he lacoperon is an example of positive gene regulation.

3hen glucose and lactose are both present,E. colipreferentially uses glucose.

)he en(ymes for glucose breakdo#n in glycolysis are al#ays present in the cell.

9nly #hen lactose is present andglucose is in short supply doesE. coliuse lactose as anenergy source and synthesi(e the en(ymes for lactose breakdo#n.

3hen glucose levels are lo#, c!clic "#$ %c"#$&accumulates in the cell.

)he regulatory protein catabolite activator protein (CAPis an activatorof transcription.

3hen c"%< is abundant, it binds to C"


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Differential gene expression is the expression of different genes by cells with the samegenome.

" typical human cell probably expresses about >=? of its genes at any given time.

@ighly speciali(ed cells, such as nerves or muscles, express only a tiny fraction of theirgenes.

"lthough all the cells in an organism contain an identical genome, the subset of genesexpressed in the cells of each type is uni/ue.

)he differences bet#een cell types are due to differential gene expression, the expression ofdifferent genes by cells #ith the same genome.

)he genomes of eukaryotes may contain tens of thousands of genes.

&or /uite a fe# species, only a small amount of the D!"A0.:? in humansAcodes forprotein.

9f the remaining D!", a very small fraction consists of genes for r!" and t!".

)he rest of the D!" either codes for !" products, such as t!"s, or isn*t transcribed.


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)istone acet!lation+addition of an acetyl group, AC9C@ and deacetylation appear toplay a direct role in the regulation of gene transcription.

"cetylated histones grip neighboring nucleosomes less tightly, providing easier access fortranscription proteins in this region.

-ome of the en(ymes responsible for acetylation or deacetylation are associated #ith or

are components of transcription factors that bind to promoters. )hus, histone acetylation en(ymes may promote the initiation of transcription not only by

modifying chromatin structure but also by binding to and recruiting components of thetranscription machinery.

-everal other chemical groups, such as methyl and phosphate groups, can be reversiblyattached to amino acids in histone tails.

)he attachment of methyl groups +AC@ to histone tails leads to condensation ofchromatin.

)he addition of a phosphate group +phosphorylation to an amino acid next to amethylated amino acid has the opposite effect.

)he recent discovery that modifications to histone tails can affect chromatin structure andgene expression has led to the histone code hypothesis.

)his hypothesis proposes that specific combinations of modifications, rather than theoverall level of histone acetylation, determine chromatin configuration.

Chromatin configuration in turn influences transcription.

D!" methylation reduces gene expression.

3hile some en(ymes methylate the tails of histone proteins, other en(ymes methylate certainbases in D!" itself.

)he D!" of most plants, animals, and fungi has methylated bases, usually cytosine.

Inactive D!" is generally highly methylated compared to D!" that is actively transcribed.

&or example, the inactivated mammalian chromosome in females is heavilymethylated.

Genes are usually more heavily methylated in cells #here they are not expressed.

Demethylating certain inactive genes turns them on.

D!" methylation proteins recruit histone deacetylation en(ymes, providing a mechanism by#hich D!" methylation and histone deacetylation cooperate to repress transcription.

In some species, D!" methylation is responsible for the long$term inactivation of genesduring cellular differentiation.

9nce methylated, genes usually stay that #ay through successive cell divisions in a givenindividual.

%ethylation en(ymes recogni(e sites on one strand that are already methylated and correctlymethylate the daughter strand after each round of D!" replication.

)his methylation pattern accounts for genomic imprinting, in #hich methylation turns offeither the maternal or paternal alleles of certain genes at the start of development.

)he chromatin modifications 'ust discussed do not alter the D!" se/uence, and yet they maybe passed along to future generations of cells.

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Inheritance of traits by mechanisms not directly involving the nucleotide se/uence is calledepigenetic inheritance.

esearchers are amassing more and more evidence for the importance of epigeneticinformation in the regulation of gene expression.

4pigenetic variations may explain #hy one identical t#in ac/uires a genetically based

disease, such as schi(ophrenia, #hile another does not, despite their identical genomes. 4n(ymes that modify chromatin structure are integral parts of the cell*s machinery for

regulating transcription.

Transcription initiation is controlled by proteins that interact with D!" and with eachother.

Chromatin$modifying en(ymes provide initial control of gene expression by making a regionof D!" either more available or less available for transcription.

" cluster of proteins called a transcription initiation comple!assembles on the promoterse/uence at the upstream end of the gene.

9ne component, !" polymerase II, transcribes the gene, synthesi(ing a primary !"

transcript or pre$m!". !" processing includes en(ymatic addition of a :cap and a poly$" tail, as #ell as splicing

out of introns to yield a mature m!".

%ultiple control elementsare associated #ith most eukaryotic genes.

Control elements are noncoding D!" segments that regulate transcription by bindingcertain proteins.

)hese control elements and the proteins they bind are critical to the precise regulation ofgene expression in different cell types.

)o initiate transcription, eukaryotic !" polymerase re/uires the assistance of proteinscalled transcription factors.

"eneral transcription factorsare essential for the transcription of allprotein$coding genes. 9nly a fe# general transcription factors independently bind a D!" se/uence such as the

)")" box #ithin the promoter.

9thers are involved in protein$protein interactions, binding each other and !"polymerase II.

9nly #hen the complete initiation complex has been assembled can the polymerase begin tomove along the D!" template strand to produce a complementary strand of !".

)he interaction of general transcription factors and !" polymerase II #ith a promoterusually leads to only a slo# rate of initiation and the production of fe# !" transcripts.

In eukaryotes, high levels of transcription of particular genes depend on the interaction of

control elements #ithspecific transcription factors. -ome control elements, namedpro!imal control elements, are located close to the promoter.

#istal control elements, enhancers, may be thousands of nucleotides a#ay from thepromoter or even do#nstream of the gene or #ithin an intron.

" given gene may have multiple enhancers, each active at a different time or in a differentcell type or location in the organism.

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Interactions bet#een enhancers and specific transcription factors called activators orrepressors are important in controlling gene expression.

"n activatoris a protein that binds to an enhancer to stimulate transcription of a gene.


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In contrast, very fe# eukaryotic genes are organi(ed this #ay.

ecent studies of the genomes of several eukaryotic species have found that some co$expressed genes are clustered near one other on the same chromosome.

4ach gene in these clusters has its o#n promoter and is individually transcribed.

)he coordinate regulation of clustered genes in eukaryotic cells is thought to involve changesin the chromatin structure that make the entire group of genes either available or unavailablefor transcription.

In other cases, including 0:? of nematode genes, several related genes share a promoter andare transcribed into a single pre$m!", #hich is then processed into separate m!"s.

%ore commonly, genes coding for the en(ymes of a metabolic path#ay are scattered overdifferent chromosomes.

Coordinate gene expression in eukaryotes depends on the association of a specific controlelement or combination of control elements #ith every gene of a dispersed group.

" common group of transcription factors binds to all the genes in the group, promotingsimultaneous gene transcription.

&or example, a steroid hormone enters a cell and binds to a specific receptor protein in thecytoplasm or nucleus, forming a hormonereceptor complex that serves as a transcriptionactivator.

4very gene #hose transcription is stimulated by that steroid hormone has a controlelement recogni(ed by that hormonereceptor complex.

9ther signal molecules control gene expression indirectly by triggering signal$transductionpath#ays that lead to activation of transcription.

)he principle of coordinate regulation is the same6 Genes #ith the same control elementsare activated by the same chemical signals.

-ystems for coordinating gene regulation probably arose early in evolutionary history andevolved by the duplication and distribution of control elements #ithin the genome.

$ost%transcriptional mechanisms play supporting roles in the control of gene expression.

Gene expression may be blocked or stimulated by any post$transcriptional step.

By using regulatory mechanisms that operate after transcription, a cell can rapidly fine$tunegene expression in response to environmental changes, #ithout altering its transcriptionalpatterns.

!" processing in the nucleus and the export of m!" to the cytoplasm provideopportunities for gene regulation that are not available in prokaryotes.

In alternative R*" splicing, different m!" molecules are produced from the sameprimary transcript, depending on #hich !" segments are treated as exons and #hich asintrons.

egulatory proteins specific to a cell type control intron$exon choices by binding toregulatory se/uences #ithin the primary transcript.

"lternative !" splicing significantly expands the repertoire of a set of genes.

)he life span of an m!" molecule is an important factor in determining the pattern ofprotein synthesis.

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%utations making specific cell cycle proteins impervious to proteasome degradation can leadto cancer.

Concept 18.+ *oncoding R*"s pla! multiple roles in controlling gene expression.

9nly 0.:? of the human genome codes for proteins. 9f the remainder, only a very small fraction consists of genes for ribosomal !" and

transfer !".

;ntil recently, it #as assumed that most of the rest of the D!" #as untranscribed. ecentdata have challenged that assumption, ho#ever.

In one study of t#o human chromosomes, it #as found that ten times as much of the genome#as transcribed as #as predicted by the number of protein$coding exons present.

Introns accounted for only a small fraction of this transcribed, nontranslated !".

" significant amount of the genome may be transcribed into nonprotein$coding !"s +ornoncoding R$As, including a variety of small !"s.

)hese discoveries suggest that there may be a large, diverse population of !" moleculesthat play crucial roles in regulating gene expression in the cell.

&icro'!"s can bind to complementary se(uences in m'!" molecules.

In the past fe# years, researchers have found small, single$stranded !" molecules calledmicroR*"s+miR*"s that bind to complementary se/uences in m!" molecules.

mi!"s are formed from longer !" precursors that fold back on themselves to form oneor more short, double$stranded hairpin structures stabili(ed by hydrogen bonding.

"n en(yme called Dicer cuts each hairpin into a short, double$stranded fragment of about >=nucleotide pairs.

9ne of the t#o strands is degraded. )he other strand +mi!" associates #ith a protein

complex and directs the complex to any m!" molecules that have a complementaryse/uence.

)he mi!"protein complex either degrades the target m!" or blocks its translation.

It is estimated that the expression of up to one$third of all human genes may be regulated bymi!"s.

)he phenomenon of inhibition of gene expression by !" molecules is called R*"interference+R*"i.

!" interference is due to small interfering !"s +si!"s, #hich are similar in si(e andfunction to mi!"s and are generated by similar mechanisms in eukaryotic cells.

Both mi!"s and si!"s can associate #ith the same proteins, #ith similar results.

)he distinction bet#een these molecules is the nature of the precursor molecules from#hich they are formed.

4ach mi!" is formed from a single hairpin in the precursor !", #hereas si!"s areformed from longer, double$stranded !" molecules that give rise to many si!"s.

Cellular !"i path#ays lead to the destruction of !"s and may have originated as anatural defense against infection by double$stranded !" viruses.

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)he fact that the !"i path#ay can also affect the expression of nonviral cellular genesmay reflect a different evolutionary origin for the !"i path#ay.

-ome species possess long, double$stranded !"s that arise from cellular genes and arecut into small !"s that block various steps in gene expression.

3hatever their origin, !"i plays an important role in regulating gene expression in the cell.

Small '!"s can remodel chromatin and silence transcription.

-mall !"s can cause remodeling of chromatin structure.

In yeast, si!"s are necessary for the formation of heterochromatin at the centromeres ofchromosomes.

4xperimental evidence suggests that an !" transcript produced from D!" in thecentromeric region of the chromosome is copied into double$stranded !" by a yeasten(yme and then processed into si!"s.

)he si!"s associate #ith a protein complex, targeting the complex back to thecentromeric se/uences of D!".

)he proteins in the complex recruit en(ymes to modify the chromatin, turning it into the

highly condensed centromeric heterochromatin.

3hen the en(yme Dicer is inactivated in chicken and mouse cells, heterochromatin failsto form at the centromeres.

elated mechanisms may also block the transcription of specific genes.

%any of the mi!"s that have been characteri(ed play important roles in embryonicdevelopment, the ultimate example of an elaborate program of regulated gene expression.

Concept 18., " program of differential gene expression leads to the different cellt!pes in a multicellular organism.

In the development of most multicellular organisms, a single$celled (ygote gives rise to cellsof many different types.

4ach type has a different structure and corresponding function.

Cells of different types are organi(ed into tissues, tissues into organs, organs into organsystems, and organ systems into the #hole organism.

)hus, the process of embryonic development must give rise not only to cells of differenttypes but also to higher$level structures arranged in a particular #ay in three dimensions.

" genetic program is expressed during embryonic development.

"s a (ygote develops into an adult organism, its transformation results from three interrelatedprocesses6 cell division, cell differentiation, and morphogenesis.

)hrough a succession of mitotic cell divisions, the (ygote gives rise to a large number ofcells.

Cell division alone #ould produce only a great ball of identical cells.

During development, cells become speciali(ed in structure and function, undergoing celldifferentiation.

Different kinds of cells are organi(ed into tissues and organs.

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)he physical processes that give an organism its shape constitute morphogenesis, theEcreation of form.F

Cell division, cell differentiation, and morphogenesis have their basis in cellular behavior.

%orphogenesis can be traced back to changes in the shape and motility of cells in thevarious embryonic regions.

)he activities of a cell depend on the genes it expresses and the proteins it produces.

Because almost all cells in an organism have the same genome, differential geneexpression results from differential gene regulation in different cell types.

3hy are different sets of activators present in different cell types5

9ne important source of information early in development is the egg*s cytoplasm, #hichcontains both !" and proteins encoded by the mother*s D!".

Cytoplasmic materials are distributed unevenly in the unfertili(ed egg.

%aternal substances that influence the course of early development are called c!toplasmicdeterminants.

)hese substances regulate the expression of genes that affect the developmental fate ofthe cell.

"fter fertili(ation, the cell nuclei resulting from mitotic division of the (ygote areexposed to different cytoplasmic environments.

)he set of cytoplasmic determinants a particular cell receives helps determine itsdevelopmental fate by regulating expression of the cell*s genes during celldifferentiation.

)he other important source of developmental information is the environment around the cell,

especially signals impinging on an embryonic cell from other nearby embryonic cells.

In animals, these signals include contact #ith cell$surface molecules on neighboring cellsand the binding of gro#th factors secreted by neighboring cells.

)hese signals cause changes in the target cells, a process called induction.

)he molecules conveying these signals #ithin the target cells are cell$surface receptorsand other proteins expressed by the embryo*s o#n genes.

)he signal molecules send a cell do#n a specific developmental path by causing a changein its gene expression that eventually results in observable cellular changes.

Cell differentiation is due to the se(uential regulation of gene expression.

During embryonic development, cells become visibly different in structure and function as

they differentiate.

)he earliest changes that set a cell on a path to speciali(ation sho# up only at the molecular

level.

%olecular changes in the embryo drive the process, called determination, that leads tothe observable differentiation of a cell.

9nce it has undergone determination, an embryonic cell is irreversibly committed to its final

fate.

Lecture Outline for Campbell/Reece Biology, 8thEdition, Pearson Education, Inc. 181"


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If a determined cell is experimentally placed in another location in the embryo, it #illdifferentiate as if it #ere in its original position.

)he outcome of determinationAobservable cell differentiationAis caused by the expression

of genes that encode tissue%specific proteins.

)hese proteins give a cell its characteristic structure and function.

Differentiation begins #ith the appearance of cell$specific m!"s and is eventuallyobservable in the microscope as changes in cellular structure.

In most cases, the pattern of gene expression in a differentiated cell is controlled at the level

of transcription.

Cells produce the proteins that allo# them to carry out their speciali(ed roles in the organism.

&or example, liver cells speciali(e in making albumin, #hile lens cells speciali(e inmaking crystalline.

-imilarly, skeletal muscle cells have high concentrations of proteins specific to muscle

tissues, such as a muscle$specific version of the contractile proteins myosin and actin.

-keletal muscle cells also have membrane receptor proteins that detect signals from nervecells.

%uscle cells develop from embryonic precursors that have the potential to develop into a

number of alternative cell types, including cartilage cells, fat cells, or multinucleate muscle

cells.


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)he secondary transcription factors activate the genes for proteins such as myosin and actin

to confer the uni/ue properties of skeletal muscle cells.

)he %yoD protein is capable of changing fully differentiated non$muscle cells into muscle

cells.

!ot allcells can be transformed by %yoD, ho#ever. !ontransforming cells may lack a combinationof regulatory proteins in addition to

%yoD.

$attern formation sets up the embryo)s body plan.

Cytoplasmic determinants and inductive signals contribute to pattern formation, the

development of spatial organi(ation in #hich the tissues and organs of an organism are all in

their characteristic places.


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)he egg forms a segmented larva, #hich goes through three larval stages. )he fly larvaforms a pupal cocoon #ithin #hich it metamorphoses into an adult fly.

In the 01=s, 4d#ard B. 7e#is demonstrated that the study of mutants can be used to

investigate#rosophiladevelopment.

7e#is studied bi(arre developmental mutations and located the mutations on the fly*s

genetic map. )his research provided the first concrete evidence that genes someho# direct the

developmental process.

In the late 01H=s, Christiane !sslein$Jolhard and 4ric 3eischaus pushed the understanding

of early pattern formation to the molecular level.

)heir goal #as to identify allthe genes that affect segmentation in#rosophila, but they facedthree problems.

&irst, because#rosophila has about 0,H== genes, there could be either only a fe# genes

affecting segmentation or so many that the pattern #ould be impossible to discern.

-econd, mutations that affect segmentation are likely to be emr!onic lethals, leading to

death at the embryonic or larval stage.

Because flies #ith embryonic lethal mutations never reproduce, they cannot be bred forstudy.

!sslein$Jolhard and 3ieschaus focused on recessive mutations that could bepropagated in hetero(ygous flies.

)hird, because of maternal effects on axis formation in the egg, the researchers also needed to

study maternal genes.

"fter exposing flies to mutagenic chemicals, !sslein$Jolhard and 3ieschaus looked fordead embryos and larvae #ith abnormal segmentation +such as t#o heads or t#o tails amongthe fly*s descendents.

)hrough appropriate crosses, they could identify living hetero(ygotes carrying embryoniclethal mutations.

)hey hoped that the segmental abnormalities #ould suggest ho# the affected genes normallyfunctioned.

!sslein$Jolhard and 3ieschaus identified 0,>== genes essential for embryonic

development.

"bout 0>= of these #ere essential for pattern formation leading to normal segmentation.

"fter several years, they #ere able to group the genes by general function, map them, and

clone many of them.

)heir results, combined #ith 7e#is*s early #ork, created a coherent picture of #rosophiladevelopment.

In 011:, !sslein$Jolhard, 3ieschaus, and 7e#is #ere a#arded the !obel


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-ubstances are produced under the direction of maternal effect genes that are deposited in the

unfertili(ed egg.

" maternal effect geneis a gene that, #hen mutant in the mother, results in a mutantphenotype in the offspring, regardless of the offspring*s o#n genotype.

In fruit fly development, maternal effect genes encode proteins or m!" that are placed in

the egg #hile it is still in the ovary.

3hen the mother has a mutation in a maternal effect gene, she makes a defective gene

product +or none at all and her eggs #ill not develop properly #hen fertili(ed.

%aternal effect genes are also called eggpolarit! genesbecause they control the orientation

of the egg and conse/uently the fly.

9ne group of genes sets up the anterior$posterior axis, #hile a second group establishes the

dorsal$ventral axis.

9ne gene called bicoidaffects the front half of the body.

"n embryo #hose mother has a mutant bicoidgene lacks the front half of its body and hasduplicate posterior structures at both ends.

)his suggests that the product of the mother*s bicoidgene is essential for setting up the

anterior end of the fly.

It also suggests that the gene*s products are concentrated at the future anterior end.

)his is a specific version of a general gradient hypothesis, in #hich gradients of morphogens

establish an embryo*s axes and other features.

;sing D!" technology and biochemical methods, researchers #ere able to clone the bicoid

gene and use it as a probe for bicoidm!" in the egg.

"s predicted, the bicoidm!" is concentrated at the extreme anterior end of the egg

cell.

&icoid m!" is produced in nurse cells, transferred to the egg via cytoplasmic bridges,and anchored to the cytoskeleton at the anterior end of the egg.

"fter the egg is fertili(ed, bicoidm!" is transcribed into Bicoid protein, #hich diffusesfrom the anterior end to#ard the posterior, resulting in a gradient of proteins in the earlyembryo.

In'ections of pure bicoidm!" into various regions of early embryos resulted in theformation of anterior structures at the in'ection sites as the m!" #as translated intoprotein.

)he bicoidresearch is important for three reasons.

0. It identified a specific protein re/uired for some of the earliest steps in pattern formation.

>. It increased our understanding of the mother*s role in the development of an embryo. "sone developmental biologist put it, E%om tells unior #hich #ay is up.F

. It demonstrated a key developmental principle6 that a gradient of molecules candetermine polarity and position in the embryo.

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Gradients of specific proteins determine the posterior end as #ell as the anterior end and also

are responsible for establishing the dorsal$ventral axis.

7ater, positional information operating at a finer scale establishes a specific number ofcorrectly oriented segments and triggers the formation of each segment*s characteristicstructures.

Concept 18./ Cancer results from genetic changes that affect cell c!clecontrol.

Cancer is a set of diseases in #hich cells escape the control mechanisms that normallyregulate cell gro#th and division.

)he gene regulation systems that go #rong during cancer are the very same systems that playimportant roles in embryonic development, the immune response, and other biologicalprocesses.

)he genes that normally regulate cell gro#th and division during the cell cycle include genesfor gro#th factors, their receptors, and the intracellular molecules of signaling path#ays.

%utations altering any of these genes in somatic cells can lead to cancer.

)he agent of such changes can be random spontaneous mutations or environmental influencessuch as chemical carcinogens, $rays, or certain viruses.

In 0100,


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"mplification increases the number of copies of the proto$oncogene in the cell.

" point mutation in the promoter or enhancer of a proto$oncogene may increase itsexpression.

" point mutation in the coding se/uence may lead to translation of a protein that is moreactive or longer$lived.

"ll of these mechanisms can lead to abnormal stimulation of the cell cycle, putting the cell onthe path to malignancy.

&utations to tumor%suppressor genes may contribute to cancer.

)he normal products of tumorsuppressor genesinhibitcell division.

"ny decrease in the normal activity of a tumor$suppressor protein may contribute to cancer.

-ome tumor$suppressor proteins normally repair damaged D!", preventing the accumulationof cancer$causing mutations.

9ther tumor$suppressor proteins control the adhesion of cells to each other or to anextracellular matrix, #hich is crucial for normal tissues and often absent in cancers.

-till others are components of cell$signaling path#ays that inhibit the cell cycle.Oncogene proteins and faulty tumor%suppressor proteins interfere with normal cell%signaling pathways.

)he proteins encoded by many proto$oncogenes and tumor$suppressor genes are componentsof cell$signaling path#ays.

%utations in the products of t#o key genes, the rasproto$oncogene and thep'tumor$suppressor gene, occur in =? and :=? of human cancers, respectively.

Both the as protein and the p: protein are components of signal$transduction path#ays thatconvey external signals to the D!" in the cell*s nucleus.

)he as protein, the product of the rasgene, is a G protein that relays a gro#th signal from agro#th factor receptor on the plasma membrane to a cascade of protein kinases.

"t the end of the path#ay is the synthesis of a protein that stimulates the cell cycle.

%any rasoncogenes have a point mutation that leads to a hyperactive version of the asprotein that can issue signals on its o#n, resulting in excessive cell division in the absence ofthe appropriate gro#th factor.

)hep,-gene, named for its :,===$dalton protein product, is a tumor$suppressor gene.

)he p: protein is a specific transcription factor for the synthesis of several cell cycle$inhibiting proteins.

)hep' gene has been called the Eguardian angel of the genome.F

Damage to the cell*s D!" acts as a signal that leads to expression of thep'gene.

)he p: protein can activate thep)*gene, #hose product halts the cell cycle by binding tocyclin$dependent kinases, allo#ing time for D!" repair.

)he p: protein can also turn on genes directly involved in D!" repair.

3hen D!" damage is irreparable, the p: protein can activate Esuicide genesF #hose proteinproducts cause cell death by apoptosis.

" mutation that knocks out the p: gene can lead to excessive cell gro#th and cancer.

Lecture Outline for Campbell/Reece Biology, 8thEdition, Pearson Education, Inc. 181'


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&ultiple mutations underlie the development of cancer.

%ore than one somatic mutation is generally needed to produce the changes characteristic ofa full$fledged cancer cell.

If cancer results from an accumulation of mutations, and if mutations occur throughout life,then the longer #e live, the more likely #e are to develop cancer.

Colorectal cancer, #ith 0:,=== ne# cases and 2=,=== deaths in the ;nited -tates each year,illustrates a multistep cancer path.

o )he first sign is often a polyp, a small benign gro#th in the colon lining.

o )he cells of the polyp look normal but divide unusually fre/uently.

o )hrough gradual accumulation of mutations that activate oncogenes and knock outtumor$suppressor genes, the polyp can develop into a malignant tumor.

" ras oncogene and a mutatedp' tumor$suppressor gene are usually involved.

"bout a half do(en D!" changes must occur for a cell to become fully cancerous.

)hese changes usually include the appearance of at least one active oncogene and the

mutation or loss of several tumor$suppressor genes. Because mutant tumor$suppressor alleles are usually recessive, mutations must knock out

bothalleles.

%ost oncogenes behave like dominant alleles and re/uire only one mutation.

In many malignant tumors, the gene for telomerase is activated, removing a natural limiton the number of times the cell can divide.

Cancer can run in families.

)he fact that multiple genetic changes are re/uired to produce a cancer cell helps explain thepredispositions to cancer that run in families.

"n individual inheriting an oncogene or a mutant allele of a tumor$suppressor gene is one

step closer to accumulating the necessary mutations for cancer to develop. Geneticists are devoting much effort to finding inherited cancer alleles so that a

predisposition to certain cancers can be detected early in life.

"bout 0:? of colorectal cancers involve inherited mutations.

o %any of these mutations affect the tumor$suppressor gene adenomatous polyposis coli,orAPC.

!ormal functions of theAPCgene include regulation of cell migration and adhesion.

4ven in patients #ith no family history of the disease,APCis mutated in about 2=? ofcolorectal cancers.

Bet#een :? and 0=? of breast cancer cases sho# an inherited predisposition.

Breast cancer is the second most common type of cancer in the ;nited -tates, annuallystriking more than 0K=,=== #omen and leading to =,=== deaths.

o %utations in one of t#o tumor$suppressor genes,&RCA*and&RCA), increase the risk ofbreast and ovarian cancer and are found in at least half of inherited breast cancers.

&RCAstands for breast cancer.

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o " #oman #ho inherits one mutant&RCA*allele has a 2=? probability of developingbreast cancer before age := +versus a >? probability in an individual #ith t#o normalalleles.

o &RCA*and&RCA)are considered tumor$suppressor genes because their #ild$typealleles protect against breast cancer and because their mutant alleles are recessive.

o ecent evidence suggests that the&RCA)protein is directly involved in repairing breaksthat occur in both strands of D!".

Because D!" breakage can contribute to cancer, the risk of cancer can be lo#ered byminimi(ing exposure to D!"$damaging agents, such as ultraviolet radiation in sunlight andthe chemicals found in cigarette smoke.

Jiruses can contribute to the development of cancer by integrating their genetic material intothe D!" of infected cells.

Jiral integration may donate an oncogene to a cell, disrupt a tumor$suppressor gene, orconvert a proto$oncogene to an oncogene.

-ome viruses produce proteins that inactivate p: and other tumor$suppressor proteins,making the cell more prone to becoming cancerous.

Lecture Outline for Campbell/Reece Biology, 8thEdition, Pearson Education, Inc. 18!1

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